Parkinson's disease (PD) is a debilitating, age-related neurological condition affecting nearly 1% of the population and growing with a projected annual cost of over $50 billion in the United States alone by 2040. The motor signs of the disease include muscular rigidity, bradykinesia, akinesia, shuffled and unstable gait, and resting tremor. Electrophysiological studies in Parkinsonian patients, 6-OHDA rats, and MPTP-treated, non- human primates have consistently found increased incidences of bursting and an increase in synchronization between basal ganglia neurons. It is likely that this abnormal activity reaches the motor cortex through the thalamus since basal ganglia output neurons strongly project to the motor thalamus. These studies have also suggested that this abnormal activity may underlie the motor symptoms seen in the disease and that interventions that disrupt this activity may be therapeutic. The difficulties in understanding the relationship between abnormal basal ganglia activity and motor dysfunction in Parkinsonian patients and in animal models of the disease is that brain activity changes in these subjects are widespread so that a link between specific basal ganglia activity and the emergence of Parkinsonian signs and symptoms cannot be made with certainty. If abnormal bursting emanating from the basal ganglia is responsible for motor dysfunction in PD then experimentally generating bursts in basal ganglia output neurons should be sufficient to cause motor dysfunction in healthy controls. The proposed research is designed to test this hypothesis in normal mice. Specifically, we will investigate the classic PD symptoms of muscular rigidity and akinesia/bradykinesia. We will first determine how motor thalamic neurons integrate bursts that are pharmacologically or optogenetically evoked in the major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNpr), in anesthetized mice during cortical slow-wave activity and a cortically-activated, desynchronized state. We will next determine how evoked bursting in the SNpr can cause rigidity using a combination of simultaneous neural and electromyographic recordings. Finally, we will also investigate how evoked SNpr bursting can cause akinesia/bradykinesia in mice performing a lever-pressing task. The contribution of the proposed research is that it will provide a detailed understanding of the relationship between abnormal burst firing in basal ganglia output nuclei and motor dysfunction. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a debilitating, age-related neurological condition with motor signs that may include muscular rigidity, bradykinesia, shuffled and unstable gait, and resting tremor. These motor symptoms may be due to abnormal bursting and oscillatory activity in the basal ganglia that is transmitted to the cortex via the motor thalamus. The proposed research will investigate how thalamic neurons integrate bursts evoked in basal ganglia output nuclei and how faithful propagation of this abnormal activity to the motor cortex can cause motor dysfunction in healthy mice.